The overall goals of this program remain the same as for the last funding period: they are to gain an increased understanding of the mechanisms of photodynamic therapy (PDT) and to optimize treatment. The unifying hypothesis of the Program Project is that the full potential of photodynamic cancer treatment cannot be realized without a comprehensive understanding of the interaction of the diverse mechanisms of molecular and cellular PDT responses. This Program Project has exceptionally broad, long-standing, multidisciplinary expertise and is uniquely qualified to attempt to develop such a comprehensive view. The specific goals are: (i) the design and development of photosensitizers targeted to the tumor to optimize efficacy and selectivity; (ii) the global characterization of PDT regimen dependent changes of the tumor microenvironment and their consequences for the regulation of molecules important for tumor growth, especially those that might act as "danger signals" for the immune system;(iii) the identification of mechanisms by which PDT alters the adaptive immune response; (iv) the optimization of response-predicting approaches, elucidation of clinical fluence rate dependent fluence-response relationships, and clinical translation of our preclinical studies with varying PDT regimens. Four individual research projects will address the following questions: 1) Can conjugation of photosensitizers to galectins, proteins that are highly expressed on the cell surface of certain malignant cells, improve PDT selectivity? 2) How does PDT regimen, which can be designed to create very different tumor microenvironments (in terms of oxygenation, cell death pathways and inflammation) and generate different molecular tumor milieus, influence the anti-tumor host response; how does PDT affect the capability of tumor cells to respond to environmental signals? 3) What are the mechanisms governing the PDT induced changes in adaptive immunity; how do different PDT regimens affect these changes? 4) Can optimizing fluence rates and utilizing tumor response-predicting approaches enhance efficacy and selectivity of clinical PDT treatment of basal cell carcinomas; can treatment outcomes be improved by biological response modifiers? The projects are supported by three scientific cores.